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Human sex chromosomes

Picture: “Human sex chromosomes” by Openi. License: CC BY 4.0

Turner syndrome

An important disorder of genital development is Turner syndrome, which involves a chromosomal aberration. It is based on monosomy of the sex chromosomes, i.e. the presence of only 1 chromosome X of the 2 sexual chromosomes. This manifests as a 45 XO karyotype with female phenotype.

Human sex chromosomes

Image: Human sex chromosomes. By Openi, License: CC BY 4.0

It is the only monosomy that is compatible with a relatively normal life. With an incidence of 1:2,500–7,500 (of females born alive), it is the most common gonadal chromosome anomaly in women. The syndrome is associated with a high rate of spontaneous abortion.

The anomaly is based on the loss of 1 sex chromosome during embryogenesis, which can happen at different stages of development (spermatogenesis or oogenesis, insemination) and is due to a nondisjunction of the chromosomes or chromatids. In 70% of the cases, it is the X chromosome of the father.

Karyotyping of a whole blood sample from a patient

Image: Karyotyping of a whole blood sample from a patient with a 45XO/47XXX karyotype, with (A) 68% 47XXX and (B) 32% 45XO. By Openi, License: CC BY 3.0

A structurally altered X chromosome can also be the cause. Furthermore, there might be chromosomal mosaicisms with inconspicuous or conspicuous cells (e.g., 46, XX/45, X0), but these have a less pronounced clinical manifestation.

While the occurrence of Turner syndrome does not correlate with the age of the mother, the older age of the father possibly plays a role in the development of the disease.

Symptoms and clinical presentation of Turner syndrome

Individuals with Turner syndrome have both a female phenotype as well as a female psychosexual identity. Cardinal symptoms are primary amenorrhea and short stature (143–147 cm). Patients are infertile and have sexual infantilism (hypoplastic female genitalia due to the lack of hormonal stimulation). While the gonads initially develop normally, they start to degenerate and fibrose in the 3rd month of pregnancy; from which moment on, the ovaries only exist as fibrous tissue, called streak gonads.

Other facultative symptoms are:

  • Short neck
  • Ptyergium colli (webbed neck)
  • Low hairline
  • Lymphedema on the back of hands and feet (in 1st weeks of life)
  • Cubitus valgus (X-shaped arms)
  • Shield chest with widely spaced nipples and funnel chest
  • Multiple (benign) pigment naevi
  • Nail and ear dysplasia
  • Malformations of the kidneys and urinary tracts
  • Malformation of the skeleton (e.g., deformities of the spine) and anomalies of the ligaments
  • Primary hypogonadism
  • Short stature
  • Osteoporosis
  • Metabolic disorders (insulin resistance, diabetes mellitus, and dyslipidemia)
  • Cardiovascular anomalies (e.g., aortic coarctation, hypertension, vasculopathy, aortic stenosis, aortic isthmus stenosis, and pulmonary vein anomalies)

These symptoms are not necessarily present all at once and maybe more or less pronounced in different individuals. The intelligence of affected individuals is normal or can be seen generally reduced partially compromising skills such as mathematics and spatial visualization.

As mentioned above, patients with mosaicism show less pronounced physical abnormalities. The degree of ovary functionality determines the development of puberty and even the possibility of spontaneous pregnancy, which, however, occurs despite an increase in the rates of abortion and congenital malformations of the child.

Diagnosis and differential diagnosis of Turner syndrome

Amenorrhea and the absence of puberty are usually the reasons why patients consult their doctor, in approx. 60–70% of cases, when the diagnosis is not made in prenatal or early postnatal life.

Because of the insufficiency of the ovaries, not enough estrogen is being produced, which makes the superior centers increase their hormone production. In an endocrinological examination, this results in increased levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and a diminished concentration of estrogen. Since this disorder occurs at the level of the gonads, it is also referred to as hypergonadotropic or primary hypogonadism.

The most suited method for making the diagnosis is a chromosome analysis which is performed on peripheral lymphocytes. With a karyogram, the karyotype of the examinee can be determined.

karyogram 45,X

Image: Karyogram 45,X. By The cat~commonswiki, License: CC BY-SA 3.0

Regarding differential diagnoses, a tumorous condition (e.g., gonadoblastoma, dysgerminoma) has to be excluded.

Treatment of Turner syndrome

Turner syndrome cannot be cured since the defect is of molecular nature (missing chromosome). Therefore, treatment will always be symptomatic, trying to enhance the physical and psychological female traits.

With the onset of puberty (around age 12–13), hormone replacement therapy should be commenced. Estrogen stimulates the growth of primary and secondary sexual characteristics (vagina, uterus, breasts, and pubic hair) and serves the prevention of osteoporosis and arteriosclerosisEstradiol valerate (1–2 mg) is often prescribed in this context. Gestagens should be taken on at least 10 days of a month to ensure proper menstruation. This transforms the endometrium instead of continuously stimulating it and thus prevents the development of endometrial carcinoma.

An early beginning of growth hormone therapy (hGH) can yield final height increments of up to 10 cm. For such a result, treatment has to start in early childhood (age 3–4).

The infertility of women affected with Turner’s syndrome is not reversible. However, they can be candidates for egg donation for those couples who wish to have children. The legal status of egg donation varies by country. While it is completely illegal in some countries (e.g., Germany), it is legal and egg donors can even be compensated in the United States.

The surgical removal of bothering stigmata (e.g., webbed neck) is an option. Furthermore, psychological counseling can be very important to the affected patients.

Complications of Turner syndrome

Women who suffer from Turner syndrome have a higher tendency than the normal population to develop cardiovascular diseases, diabetes mellitus, thyroid disorders, and inflammatory diseases of the intestine.

The life expectancy of the affected individuals can be reduced by 13 years on average.

Adrenogenital syndrome (AGS)

Definition, epidemiology, and etiology of AGS

The adrenogenital syndrome (AGS) is the most common cause of feminine pseudohermaphroditism (chromosomal and gonadal female, male habitus). It comprises a group of diseases that stem from a genetic defect of enzymes of the cortisol synthesis in the adrenal cortex. The result of these enzymatic defects is an increased production of male sexual hormones (androgens) with virilization of the outer female genitals.

The autosomal recessive disease has an incidence of 1:5,000–1:15,000.

Classification of AGS

Generally, every enzyme involved in cortisol synthesis can be affected by a defect. The clinical presentation varies depending on the affected enzyme. The following enzymes are most frequently affected:

  • 21-hydroxylase
  • 3-beta-hydroxysteroid-dehydrogenase
  • 11-beta-hydroxylase

The damage of the enzyme may be complete or incomplete, which accordingly results in differently pronounced clinical manifestations (see below).

Since the 21-hydroxylase deficiency is the most frequent cause in approx. 95% of cases, it will be the focus of the following discussion.

Pathophysiology of AGS

Because of the 21-hydroxylase deficiency, cortisol is not produced at all or only in a very small amount. Since there is no negative feedback in the superior hormone control centers, this results in an increased release of adrenocorticotropic hormone (ACTH) from the hypophysis. This hormone stimulates the adrenal cortex to the point where it becomes hyperplastic (congenital adrenal hyperplasia, CAH).

This results in an increased production of androgens and an accumulation of intermediate products, which can again be utilized in further androgen synthesis.

Congenital adrenal hyperplasia

Image: Congenital adrenal hyperplasia. By StarBuG, License: CC BY-SA 3.0

Enzymes, their cellular location, substrates and products in human steroidogenesis

Image: Enzymes, their cellular location, substrates, and products in human steroidogenesis. By David Richfield and Mikael Häggström, License: CC BY-SA 3.0

Symptoms and clinical presentation of AGS

In the following, the effects of the disease on the female patient will be described.

Patients have karyotype 46, XX and normally developed female inner genitals. However, there is masculinization (virilization) of the outer genitals, which can be manifested to varying degrees depending on the time and severity of the excess androgen production. The manifestations reach from sole hypertrophy of the clitoris to fusion of the labioscrotal folds and the development of male urethra.

The time of manifestation is also variable and can fall into the fetal period, childhood, or in or after puberty.

The classic childhood-onset simple virilizing 21-hydroxylase deficiency already manifests in the prenatal period as virilization of the female fetuses; at birth, the outer genitalia can be masculinized to varying degrees.

Morphotype masculin

Image: Morphotype masculine. By Openi, License: CC BY 2.0

If the condition is left untreated, pubic and axillary hair will begin to grow already in the 2nd year of life. The affected children are also taller than other children of the same age. This, however, is reversed in adolescence and adulthood as the epiphyseal plates close prematurely and patients will be shorter than other adults. In addition to the body hair (hirsutism) like men, patients can experience a change of voice with more severe tones and because the patients do not present a classic female puberty, therefore, suffer from amenorrhea and infertility.

Subject photo before use of omega-3 poly-nutrient capsules (acne vulgaris)

Image: Subject photo before the use of omega-3 poly-nutrient capsules (acne vulgaris). By Openi, License: CC BY 2.0

The non-classic 21-hydroxylase deficiency (late-onset CAH) manifests later in life; at birth, the affected girl babies appear inconspicuous. The onset of the disease during puberty is characterized by a mild form of virilization (possibly acne, hirsutism, and seborrhea). Also, patients may experience menstrual disorders with prolonged menstrual cycles or amenorrhea.


Image: Hirutismus. By Openi, License: CC BY 2.0

In some cases, the synthesis of aldosterone may also be impaired, which can result in a salt-wasting crisis including dehydration, hyponatremia, hypokalemia, and acidosis. The affected infants are apathetic, develop severe vomiting, and need immediate treatment—if not, the condition can rapidly cause death.

Diagnosis and differential diagnosis of AGS

A 21-hydroxylase deficiency can be confirmed by performing an ACTH stimulation test: First, the patient must fast for at least 6 hours, and the basal serum levels of 17-hydroxyprogesterone (17-OHP) and cortisol are measured. Then, ACTH is injected intravenously (250 mg). One hour after the ACTH injection, 17-OHP and cortisol are measured again. In healthy individuals, the difference between the 1st and the 2nd measuring of 17-OHP should not exceed 2.5 ng/ml. Any increase higher than that is diagnostic of CAH.

Treatment of AGS


Image: Moon facies with hypertrichosis over forehead and lips (Cushing’s syndrome). By Openi, License: CC BY 2.5

Treatment of CAH should start as early as possible to prevent any further virilization of the patient and to maintain a normalized ovarian function. Affected individuals will have to undergo life-long glucocorticoid replacement (e.g., with hydrocortisone or dexamethasone). This reduced the ACTH production and thus, the formation of androgens. The treatment has to be adjusted to each patient individually to avoid the occurrence of Cushing’s syndrome or growth failure. With sufficient treatment, normal development of the woman can be achieved and even infertility can be reversed so that pregnancy becomes viable. Healthy offspring will however, be carriers of CAH.

NOTE: Excess exposure to glucocorticoids can lead to Cushing’s syndrome!

Patients with a salt-wasting form of CAH have to be administered mineralocorticoids (e.g., fludrocortisone), and the associated electrolyte imbalances have to be remedied.

Symptoms of Cushing’s syndrome

Image: Symptoms of Cushing’s syndrome. By Mikael Häggström, License: CC0 1.0

Prevention of AGS

The disease is of autosomal recessive inheritance. This means that if a mother has had 1 child with AGS, there is a probability of 25% for the next child to also have AGS. Administration of dexamethasone (1–1.5 mg/dL) during pregnancy can prevent the virilization of a diseased infant. If male genitalia are detected or AGS can be ruled out through prenatal diagnostics at a later point of the pregnancy, the administration of dexamethasone can be stopped.

Androgen insensitivity syndrome (AIS)

The androgen insensitivity syndrome (AIS) is a form of masculine “pseudohermaphroditism” (genetic and gonadal male, female habitus). Due to a receptor defect, the affected individuals are unresponsive to androgen which results in the development of female external genitalia.

AIS stems from a mutation of the androgen receptor gene. This gene is located on the X chromosome, which gives the disease an X-linked recessive mode of inheritance.


Location and structure of the human androgen receptor

Image: Location and structure of the human androgen receptor. By Jonathan Marcus, License: CC BY-SA 3.0

The incidence of this condition is 1:20,000.

Classification of AIS

Inheritance of androgen insensitivity syndrome in the family.

Image: Inheritance of androgen insensitivity syndrome in the family. Family pedigree (A). Female genitalia with palpable gonads in the index case III-10 (B) and her niece IV-1 (C). By Openi, License: CC BY 2.0

Based on the phenotype, AIS is classified as either complete androgen insensitivity syndrome (CAIS) or as partial androgen insensitivity syndrome (PAIS). The latter is indicated when the androgen resistance is only incomplete and the development of the external genitalia is highly variable (ambiguous, male, or female).

The following sections deal with complete androgen insensitivity syndrome.

Symptoms and clinical presentation of androgen insensitivity syndrome

Affected individuals have karyotype 46, XY and male gonads (testes). The testes are located either within the abdomen, in the inguinal rings, or the labia majora.

Due to a genetic defect of the testosterone receptors in the target tissues, the testosterone produced by the testes cannot be effective. This results in female external genitalia, which is why the affected individuals are raised as girls. In puberty, the condition becomes noticeable since there are no internal female sex organs (ovaries, fallopian tubes, and uterus), which consequently leads to amenorrhea and infertility. The outer appearance of patients is characterized by a tall, slender stature. Breast development is not impaired. A further sign is absent secondary terminal hair (axillary and pubic hair). The vagina is often short and blind-ended.

Diagnosis of AIS

Patients will usually present because of absent menstruation. The suitable diagnostic method is a chromosome analysis, which can reveal the male genotype standing in contrast to the female habitus. Furthermore, testosterone levels will be in the normal male range, but estrogen levels will be too low for a woman.

Treatment of AIS

Patients usually identify as female. The diagnosis used to be hidden from the affected children, but current practice is the age-appropriate disclosure by the parents and psychological counseling. Patients are capable of cohabitation but remain infertile.

A. Laparoscopic View of the Left Gonad; B. The Right Gonad; C. Gross Image of the Removed Gonads

Image: A. Laparoscopic view of the left gonad; B. The right gonad; C. Gross image of the removed gonads. By Openi, License: CC BY 3.0

The standard of care is the post-pubertal surgical removal of the testes (orchidectomy) to prevent a malign degeneration, followed by hormone replacement therapy with estrogen and gestagen. Some patients with a short vagina or vaginal aplasia may also require surgical corrective treatment.

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